Could platelet mass index (PMI) be a new prognostic biomarker for COVID-19?

Aim: Although most patients with COVID-19 experience respiratory tract infections, severe reactions to the virus may cause coagulation abnormalities that mimic other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation and thrombotic microangiopathy. Fluctuations in platelet markers, which are an indicator of the acute phase response for COVID-19, are of clinical importance. The aim of this study is to evaluate the relationship between disease severity and Platelet Mass Index (MPI) parameters in COVID-19 patients. Material(s) and Method(s): This retrospective observational study was conducted with patients who were diagnosed with COVID-19 in a tertiary hospital. The study was continued with the remaining 280 patients. All laboratory data were scanned retrospectively from patient files and hospital information system. Result(s): A very high positive correlation was found between PMI and PLT. The PMI value in women was significantly higher than in men. It was observed that PMI did not differ significantly in terms of mortality, intubation, CPAP and comorbidity. PMI vs. Pneumonia Ct Severity Score, biochemistry parameters (AST, CRP), hemogram parameters (WBC, HGB, HCT, MCV, LYM, MPV EO) and coagulation factors (aPTT and FIB) at various levels of positive/negative, weak and strong, and significant relationship was found. There was no significant relationship between hormone and D-dimer when compared with PMI. Discussion(s): Although platelet count alone does not provide information about the prognosis of the disease, PMI may guide the clinician as an indicator of lung damage in seriously ill patients.Copyright © 2022, Derman Medical Publishing. All rights reserved.

Case report: COVID-19-associated refractory thrombotic thrombocytopenic purpura complicated with Guillain-Barré syndrome.

Thrombotic thrombocytopenic purpura (TTP), a rare and lethal thrombotic microangiopathy, is an autoimmune disease that can be triggered by viral infections such as COVID-19. This condition is characterized by hemolytic microangiopathy, thrombocytopenia, and neurologic alterations, possibly accompanied by fever and renal damage. Moreover, more than 220 patients with Guillain-Barré syndrome (GBS) have been reported in association with the COVID-19 infection. In this report, we present a case of a patient who developed refractory TTP complicated by GBS following a SARS-CoV-2 infection. We aimed to highlight the importance of accurately diagnosing neurological complications associated with a COVID-19 infection and to demonstrate our strategies for treating a patient with COVID-19 infection-related refractory TTP complicated by GBS.

Erratum: Immune-mediated thrombotic thrombocytopenic purpura following mRNA-based COVID-19 vaccine BNT162b2: Case report and mini-review of the literature.

[This corrects the article DOI: 10.3389/fmed.2022.890661.].

Comparison of Vitamin D and Resveratrol Performances in COVID-19.

Over the last few years, we have experienced the infection generated by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) often resulting in an exaggerated immune reaction and systemic inflammation. The preferred treatments against SARS-CoV-2 were those that mitigated immunological/inflammatory dysfunction. A variety of observational epidemiological studies have reported that vitamin D deficiency is often a crucial factor in many inflammatory diseases and autoimmune diseases, as well as the susceptibility to contract infectious diseases, including acute respiratory infections. Similarly, resveratrol regulates immunity, modifying the gene expression and the release of proinflammatory cytokines in the immune cells. Therefore, it plays an immunomodulatory role that can be beneficial in the prevention and development of non-communicable diseases associated with inflammation. Since both vitamin D and resveratrol also act as immunomodulators in inflammatory pathologies, many studies have paid particular attention to an integrated treatment of either vitamin D or resveratrol in the immune reaction against SARS-CoV-2 infections. This article offers a critical evaluation of published clinical trials that have examined the use of vitamin D or resveratrol as adjuncts in COVID-19 management. Furthermore, we aimed to compare the anti-inflammatory and antioxidant properties linked to the modulation of the immune system, along with antiviral properties of both vitamin D and resveratrol.

Diabetic Ketoacidosis Complicated by Thrombotic Thrombocytopenic Purpura: A Rare Association.

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially life-threatening blood disorder caused by a deficiency or dysfunction of ADAMTS13 and can occur secondary to various conditions, including autoimmune diseases, infections, medications, pregnancy, and malignancies. Diabetic ketoacidosis (DKA) inducing TTP is uncommon and not widely reported in the literature. Herein, we report a case of TTP induced by DKA in an adult patient. His clinical picture, serological, and biochemical results confirmed the diagnosis of TTP induced by DKA, and his clinical course did not improve despite normalization of glucose level, plasmapheresis, and aggressive management. Our case report emphasizes the importance of considering TTP as a potential complication of DKA.

A case report of vaccine-induced immune thrombotic thrombocytopenia (VITT) with genetic analysis.

The emergence of the rare syndrome called vaccine-induced immune thrombocytopenia and thrombosis (VITT) after adenoviral vector vaccines, including ChAdOx1 nCov-19, raises concern about one's predisposing risk factors. Here we report the case of a 56-year-old white man who developed VITT leading to death within 9 days of symptom onset. He presented with superior sagittal sinus thrombosis, right frontal intraparenchymal hematoma, frontoparietal subarachnoid and massive ventricular hemorrhage, and right lower extremity arterial and venous thrombosis. His laboratory results showed elevated D-dimer, C-reactive protein, tissue factor, P-selectin (CD62p), and positive anti-platelet factor 4. The patient's plasma promoted higher CD62p expression in healthy donors' platelets than the controls. Genetic investigation on coagulation, thrombophilia, inflammation, and type I interferon-related genes was performed. From rare variants in European or African genomic databases, 68 single-nucleotide polymorphisms (SNPs) in one allele and 11 in two alleles from common SNPs were found in the patient genome. This report highlights the possible relationship between VITT and genetic variants. Additional investigations regarding the genetic predisposition of VITT are needed.

Whole Blood Procoagulant Platelet Flow Cytometry Protocol for Heparin-Induced Thrombocytopenia (HIT) and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT) Testing.

Heparin-induced thrombocytopenia (HIT) is a well-characterized, iatrogenic complication of heparin anticoagulation with significant morbidity. In contrast, vaccine-induced immune thrombotic thrombocytopenia (VITT) is a recently recognized severe prothrombotic complication of adenoviral vaccines, including the ChAdOx1 nCoV-19 (Vaxzevria, AstraZeneca) and Ad26.COV2.S (Janssen, Johnson & Johnson) vaccines against COVID-19. The diagnosis of HIT and VITT involve laboratory testing for antiplatelet antibodies by immunoassays followed by confirmation by functional assays to detect platelet-activating antibodies. Functional assays are critical to detect pathological antibodies due to the varying sensitivity and specificity of immunoassays. This chapter presents a protocol for a novel whole blood flow cytometry-based assay to detect procoagulant platelets in healthy donor blood in response to plasma from patients suspected of HIT or VITT. A method to identify suitable healthy donors for HIT and VITT testing is also described.

Multiple Electrode Aggregometry (Multiplate): Functional Assay for Vaccine-Induced (Immune) Thrombotic Thrombocytopenia (VITT).

Vaccine-induced immune thrombotic thrombocytopenia (VITT) was first described in 2021 and represents an adverse reaction to adenoviral vector COVID-19 vaccines AstraZeneca ChAdOx1 nCoV-19 (AZD1222) and Johnson & Johnson Ad26.COV2.S vaccine. VITT is a severe immune platelet activation syndrome with an incidence of 1-2 per 100,000 vaccinations. The features of VITT include thrombocytopenia and thrombosis within 4-42 days of first dose of vaccine. Affected individuals develop platelet-activating antibodies against platelet factor 4 (PF4). The International Society on Thrombosis and Haemostasis recommends both an antigen-binding assay (enzyme-linked immunosorbent assay, ELISA) and a functional platelet activation assay for the diagnostic workup of VITT. Here, the application of multiple electrode aggregometry (Multiplate) is presented as a functional assay for VITT.

Serotonin Release Assay: Functional Assay for Heparin- and Vaccine-Induced (Immune) Thrombotic Thrombocytopenia.

The serotonin release assay (SRA) has been the gold-standard assay for detection of heparin-dependent platelet-activating antibodies and integral for the diagnosis for heparin-induced thrombotic thrombocytopenia (HIT). In 2021, a thrombotic thrombocytopenic syndrome was reported after adenoviral vector COVID-19 vaccination. This vaccine-induced thrombotic thrombocytopenic syndrome (VITT) proved to be a severe immune platelet activation syndrome manifested by unusual thrombosis, thrombocytopenia, very elevated plasma D-dimer, and a high mortality even with aggressive therapy (anticoagulation and plasma exchange). While the platelet-activating antibodies in both HIT and VITT are directed toward platelet factor 4 (PF4), important differences have been found. These differences have required modifications to the SRA to improve detection of functional VITT antibodies. Functional platelet activation assays remain essential in the diagnostic workup of HIT and VITT. Here we detail the application of SRA for the assessment of HIT and VITT antibodies.

High-Dose Prophylactic Anticoagulation for COVID-19 Pneumonia: A Review of Benefits and Risks.

The COVID-19 pandemic has had a devastating impact on a global scale, causing significant morbidity and mortality. The virus affects multiple organ systems, including the respiratory, cardiovascular, and coagulation systems, leading to severe pneumonia in some patients. Moreover, COVID-19 patients with severe pneumonia have a high incidence of thrombotic events, which can result in significant morbidity and mortality. Given the potential benefits of anticoagulation therapy in COVID-19 patients with thrombotic complications, recent studies have proposed high-dose prophylactic anticoagulation (HD-PA) therapy as a potential treatment option. In fact, some studies have suggested that HD-PA therapy may be more effective in reducing thrombotic events and mortality rates than other treatment options. This review aims to provide a comprehensive overview of the benefits and risks of HD-PA therapy for COVID-19 pneumonia patients. By synthesizing and analyzing the latest available research, we highlight patient selection criteria and discuss the optimal dosage, duration, and timing of therapy. Additionally, we review the potential risks associated with HD-PA therapy and provide recommendations for clinical practice. Ultimately, this review provides valuable insights into the use of HD-PA therapy in COVID-19 pneumonia patients and paves the way for further research in this critical area. By exploring the benefits and risks of this treatment option, we hope to provide healthcare professionals with the information they need to make informed decisions about the best course of treatment for their patients.

Heparin-Induced Thrombotic Thrombocytopenia (HITT) and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Similar but Different.

Heparin-induced thrombocytopenia (HIT) represents an autoimmune process whereby antibodies are formed against heparin in complex with platelet factor 4 (PF4) after heparin administration. These antibodies can be detected by a variety of immunological assays, including ELISA (enzyme-linked immunosorbent assay) and by chemiluminescence on the AcuStar instrument. However, pathological HIT antibodies are those that activate platelets in a platelet activation assay and cause thrombosis in vivo. We would tend to call this condition heparin-induced thrombotic thrombocytopenia (HITT), although some workers instead use the truncated abbreviation HIT. Vaccine-induced (immune) thrombotic thrombocytopenia (VITT) instead reflects an autoimmune process whereby antibodies are formed against PF4 after administration of a vaccine, most notably adenovirus-based vaccines directed against COVID-19 (coronavirus disease 2019). Although both VITT and HITT reflect similar pathological processes, they have different origins and are detected in different ways. Most notable is that anti-PF4 antibodies in VITT can only be detected immunologically by ELISA assays, tending to be negative in rapid assays such as that using the AcuStar. Moreover, functional platelet activation assays otherwise used for HITT may need to be modified to detect platelet activation in VITT.

Automated and Rapid ADAMTS13 Testing Using Chemiluminescence: Utility for Identification or Exclusion of TTP and Beyond.

Thrombotic thrombocytopenic purpura (TTP) is a prothrombotic condition caused by a significant deficiency of the enzyme, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). In the absence of adequate levels of ADAMTS13 (i.e., in TTP), plasma VWF accumulates, in particular as "ultra-large" VWF multimers, and this leads to pathological platelet aggregation and thrombosis. In addition to TTP, ADAMTS13 may be mildly to moderately reduced in a range of other conditions, including secondary thrombotic microangiopathies (TMA) such as those caused by infections (e.g., hemolytic uremic syndrome (HUS)), liver disease, disseminated intravascular coagulation (DIC), and sepsis, during acute/chronic inflammatory conditions, and sometimes also in COVID-19 (coronavirus disease 2019)). ADAMTS13 can be detected by a variety of techniques, including ELISA (enzyme-linked immunosorbent assay), FRET (fluorescence resonance energy transfer) and by chemiluminescence immunoassay (CLIA). The current report describes a protocol for assessment of ADAMTS13 by CLIA. This protocol reflects a rapid test able to be performed within 35 min on the AcuStar instrument (Werfen/Instrumentation Laboratory), although certain regional approvals may also permit this testing to be performed on a BioFlash instrument from the same manufacturer.

Complement-Mediated Thrombotic Microangiopathy Related to COVID-19 or SARS-CoV-2 Vaccination.

Introduction: Infectious diseases and vaccinations are trigger factors for thrombotic microangiopathy. Consequently, the COVID-19 pandemic could have an effect on disease manifestation or relapse in patients with atypical hemolytic syndrome/complement-mediated thrombotic microangiopathy (aHUS/cTMA). Methods: We employed the Vienna TMA cohort database to examine the incidence of COVID-19 related and of SARS-CoV-2 vaccination-related relapse of aHUS/cTMA among patients previously diagnosed with aHUS/cTMA during the first 2.5 years of the COVID-19 pandemic. We calculated incidence rates, including respective confidence intervals (CIs) and used Cox proportional hazard models for comparison of aHUS/cTMA episodes following infection or vaccination. Results: Among 27 patients with aHUS/cTMA, 13 infections triggered 3 (23%) TMA episodes, whereas 70 vaccinations triggered 1 TMA episode (1%; odds ratio 0.04; 95% CI 0.003-0.37, P = 0.01). In total, the incidence of TMA after COVID-19 or SARS-CoV-2 vaccination was 6 cases per 100 patient years (95% CI 0.017-0.164) (4.5/100 patient years for COVID-19 and 1.5/100 patient years for SARS-CoV-2 vaccination). The mean follow-up time was 2.31 ± 0.26 years (total amount: 22,118 days; 62.5 years) to either the end of the follow-up or TMA relapse (outcome). Between 2012 and 2022 we did not find a significant increase in the incidence of aHUS/cTMA. Conclusion: COVID-19 is associated with a higher risk for aHUS/cTMA recurrence when compared to SARS-CoV-2 vaccination. Overall, the incidence of aHUS/cTMA after COVID-19 infection or SARS-CoV-2 vaccination is low and comparable to that described in the literature.

Drug-induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data.

Many medications have been reported to be associated with thrombotic thrombocytopenic purpura (TTP) through pharmacovigilance data and published case reports. Whilst there are existing data available regarding drug-induced thrombotic microangiopathy, there is no available synthesis of evidence to assess drug-induced TTP (DI-TTP). Despite this lack of evidence, patients with TTP are often advised against using many medications due to the theoretical risk of DI-TTP. This systematic review evaluated the evidence for an association of medications reported as potential triggers for TTP. Of 5098 records available 261 articles were assessed further for eligibility. Fifty-seven reports, totalling 90 patients, were included in the final analysis. There were no cases where the level of association was rated as definite or probable, demonstrating a lack of evidence of any drug causing DI-TTP. This paucity of evidence was also demonstrated in the pharmacovigilance data, where 613 drugs were reported as potential causes of TTP without assessment of the strength of association. This systematic review demonstrates the need for standardised reporting of potential drugs causing TTP. Many reports omit basic information and, therefore, hinder the chance of finding a causative link if one exists.

The winding 12-month journey of the AstraZeneca COVID-19 vaccine since its first administration to humans.

The deficiently designed and conducted initial clinical development plan and the occurrence of thrombotic thrombocytopenia cases, have marked the 12-month journey of the AstraZeneca coronavirus disease 2019 (COVID-19) vaccine after it was first administered to humans. When it was authorized, there were no available efficacy data in the elderly. However, this age group was included in the product labelling based on immunogenicity data. The lack of safety and efficacy data in the elderly that was acknowledged in the product information, triggered most European Union (EU) countries to limit the administration of this vaccine to certain age groups. In February-March/2021, after the results of observational studies supported the vaccine effectiveness in the elderly, several countries broadened its use to this age group. When trust on the vaccine was ramping up, unusual blood clot cases were described in Europe, which led 24 countries around the world to temporarily halt its administration. These cases were first described as thrombotic thrombocytopenia in late March. In mid-April, the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) updated the product information and confirmed the positive benefit/risk ratio of the vaccine, recommending its use with no age restrictions. The World Health Organization (WHO) coincided with this approach. However, several countries decided to limit its use to certain age groups. The EMA listed thrombotic thrombocytopenia as a "very rare" adverse reaction. Although, the AstraZeneca vaccine was conceived in early 2020 to be a worldwide leader in the fight against COVID-19, its use was abandoned by the African Union, Denmark, and Israel. However, this vaccine has shown its usefulness in many settings across the world.

Covax-19/Spikogen: The first exclusively Australian-developed human vaccine in four decades

Introduction/Aim: The development of safe and effective vaccines is crucial to conquering the COVID-19 pandemic. Recombinant proteins represent the best understood and reliable approach to pandemic vaccine delivery with well-established safety;however, they face challenges in design, structural characterisation, manufacture, potency testing and ensuring adequate immunogenicity. Method(s): Our team used in silico structural modelling to design a vaccine based on a stabilised spike protein extracellular domain (ECD). The insect cell expressed recombinant spike ECD was formulated with Vaxine's proprietary Advax-CpG55.2 adjuvant. Result(s): The vaccine known as Covax-19 or SpikoGen induced high titers of antibody and memory T-cells which translated to protection against SARS-CoV-2 infection in hamsters, ferrets, and aged monkeys. Despite numerous challenges along the journey, clinical trials in Iran during a major wave of delta variant infection confirmed SpikoGen vaccine was 78% effective in reducing risk of severe disease and with no evidence of vaccine-associated thrombosis, myocarditis, or sudden death, receiving marketing approval under emergency use authorisation in Iran on 6 October 2021. This made it the first recombinant spike-protein vaccine in the world to be approved, and the first Australian-developed human vaccine to receive marketing approval in four decades. Since approval millions of doses have been administered and additional trials in Australia and Iran have confirmed its effectiveness as a booster to prevent waning immunity, as well as its safety and effectiveness in children from the age of 5 years. The ongoing Australian and overseas clinical trial program is focussed on gaining better understanding the effect of dosing intervals on vaccine immunogenicity, gathering additional data on use as a booster, and development of new variant formulations. Conclusion(s): Covax-19/Spikogen is safe and effective adjuvanted recombinant protein vaccine.

Coagulopathy: A Vicious Indicator of COVID-19

COVID-19 is routinely associated with coagulopathy and complications associated with thrombosis. However, the difference between the coagulopathy, which is associated with COVID-19 and the coagulopathy, which is due to different causes, is that the "COVID-19 associated coagulopathy" shows raised levels of D-Dimer and that of fibrinogen. However, it shows quite some abnormalities in the levels of prothrombin time and also in the platelet count. "Venous thromboembolism" and arterial thrombosis is frequently seen in COVID-19 associated coagulopathy as opposed to "disseminated intravascular coagulopathy". Patients suffering from COVID-19 have many have multiple factors in common for thromboembolism which is associated with "Adult respiratory distress syndrome" from different etiologies like generalized inflammation and being unambulatory. "Cytokine storm" is the hallmark of COVID-19 associated coagulopathy which is distinguished by high levels of IL-6,1, tumour necrosis factor and other cytokines. The clinical features of COVID-19 associated coagulopathy overlap that of some syndromes like antiphos-pholipid syndrome and thrombotic microangiopathy. Studies have shown that patients diagnosed with disseminated intravascular coagulation have a poor prognosis compared to the one's that don't get diagnosed with DIC. The advancement of the condition from coagulopathy in the vasculature of the lungs to DIC in patients who have tested positive for COVID-19 shows that the patient's dysfunction associated with coagulation has evolved from local to generalized state. Investigating the coagulopathies will help in understanding the mechanism of COVID-19 associated coagulopathy.Copyright © International Journal of Research in Pharmaceutical Sciences.

Simultaneous systemic thrombosis as a manifestation of COVID-19.

BACKGROUND: The current COVID-19 pandemic mainly affects the respiratory system;however, with the increase in cases worldwide, there is evidence of compromise at the cardiovascular level, which can manifest as acute myocardial infarction, myocarditis, pericarditis, myopericarditis, heart failure, cardiogenic shock, vasculitis, deep vein thrombosis, pulmonary embolism, ischemic stroke, acute arterial insufficiency, arrhythmias, and sudden death. CLINICAL CASE: A 70-year-old male patient who simultaneously presented multisystemic thrombosis manifested by cerebral vascular event, pulmonary thromboembolism, acute myocardial infarction and acute arterial insufficiency in the context of SARSCoV-2 pneumonia. CONCLUSION(S): In patients with COVID-19 there is a high thrombogenic potential secondary to blood stasis, hypercoagulability and endothelial dysfunction, which worsens the prognosis and increases mortality, mainly in patients who require ICU stay, so an adequate thromboprophylactic or anticoagulant scheme and follow-up in the convalescent phase must be provided to detect sequelae associated with COVID-19.Copyright © 2022 Comunicaciones Cientificas Mexicanas S.A. de C.V.. All rights reserved.